Opioid use disorders (OUD) and overdose are public health threats worldwide. Widespread access to highly potent illicit synthetic opioids such as fentanyl is driving the recent rise in fatal overdoses. Vaccines containing fentanyl-based haptens conjugated to immunogenic carrier proteins offer a long-lasting, safe, and cost-effective strategy to protect individuals from overdose upon accidental or deliberate exposure to fentanyl and its analogs. Prophylactic or therapeutic active immunization with an anti-fentanyl vaccine induces the production of fentanyl-specific antibodies that bind the drug in the blood and prevent its distribution to the brain, which reduces its reinforcing effects and attenuates respiratory depression and bradycardia. To increase the efficacy of a lead anti-fentanyl vaccine, this study tested whether the incorporation of synthetic toll-like receptor (TLR) 4 and TLR7/8 agonists as vaccine adjuvants would increase vaccine efficacy against fentanyl challenge, overdose, and self-administration in either rats or Hanford miniature pigs. Formulation of the vaccine with a nucleolipid TLR7/8 agonist enhanced its immunogenicity and efficacy in preventing fentanyl-induced respiratory depression, analgesia, bradycardia, and self-administration in either rats or mini-pigs. These studies support the use of TLR7/8 adjuvants in vaccine formulations to improve their clinical efficacy against OUD and potentially other substance use disorders (SUD).

阿片类药物使用障碍 (OUD) 和过量服用是全世界公共卫生的威胁。芬太尼等强效非法合成阿片类药物的广泛使用正在推动近期致命过量用药的增加。含有与免疫原性载体蛋白缀合的基于芬太尼的半抗原的疫苗提供了一种持久、安全且具有成本效益的策略，以保护个体在意外或故意接触芬太尼及其类似物时免于过量服用。使用抗芬太尼疫苗进行预防性或治疗性主动免疫会诱导芬太尼特异性抗体的产生，这些抗体与血液中的药物结合并阻止其分布到大脑，从而降低其增强作用并减轻呼吸抑制和心动过缓。为了提高主要抗芬太尼疫苗的功效，本研究测试了将合成 Toll 样受体 (TLR) 4 和 TLR7/8 激动剂掺入作为疫苗佐剂是否会提高针对芬太尼激发、过量服用和自我给药的疫苗功效在大鼠或汉福德小型猪中。含有核脂 TLR7/8 激动剂的疫苗配方增强了其免疫原性和预防芬太尼诱导的大鼠或小型猪呼吸抑制、镇痛、心动过缓和自我给药的功效。这些研究支持在疫苗配方中使用 TLR7/8 佐剂，以提高其针对 OUD 和潜在的其他物质使用障碍 (SUD) 的临床疗效。